Much research in the area of biopharmaceutics is directed toward the development of effective implantable vehicles for drug delivery and other surgical applications. Such vehicles must be biocompatible and also must be capable of protecting the activity of any biologically active agent they are intended to deliver. Many biologically active agents are labile and easily lose activity when they are incorporated into a delivery material. Preservation of protein activity has posed particularly difficult problems.
In the drug delivery arena, calcium phosphate ceramics have been studied as potential delivery vehicles due to their well known biocompatibility and their affinity for protein reagents (see, e.g., Ijntema et al, Int. J. Pharm. 112:215 (1994); Itokazu et al., J. Orth. Res. 10:440 (1992); Shinto et al., J. Bone Joint Surg. 74-B:600 (1992); and Uchida et al., J. Orth. Res. 10:440 (1992)). Most of these materials have been in the form of prefabricated, sintered hydroxyapatite in either granule or block forms. These preparations have several drawbacks, including a limited ability to conform to skeletal defects, particularly in the case of blocks; inadequate structural integrity of granules (which do not bond together); and difficulty in modeling the implant to the shape of missing skeletal tissue with both blocks and granules. The block form of hydroxyapatite provides structural support, but among other complications, must be held in place by mechanical means, which greatly limits its use and its cosmetic results. Also, it is very difficult to saw a hydroxyapatite block into a shape that fits the patient's individual defect. The granular form produces cosmetically better results, but has a very limited structural stability and is difficult to contain during and after a surgical procedure. In general, all of these products are ceramics, produced by high temperature sintering, and are not individually crystalline, but rather have their crystal boundaries fused together. Most ceramic-type materials are in general functionally biologically non-absorbable (having an absorption rate generally not exceeding on the order of 1% per year).
A porous, non-resorbable material based on coral allows intergrowth with bone, but ultimately becomes only approximately 20% bone with the remaining 80% subsisting as scar tissue. HA RESORB® made by Osteogen is a form of absorbable hydroxyapatite, but is not a cement. It is granular and not adhesive. HA RESORB® is loosely rather than adhesively packed into place. For large uses, it is replaced by bone too quickly. In the dental materials market, HAPSET® is a composition of calcium phosphate granules and cementable plaster of Paris (calcium sulfate). This material is not truly a hydroxyapatite and contains too much calcium sulfate for most biological uses. The calcium sulfate component of such a composition is resorbable, but not the calcium phosphate granules.
At least one class of calcium phosphate compositions are precursors for the formation of hydroxyapatite and are biologically compatible, and have two unique properties that are not attainable in other calcium phosphate biomaterials: (1) self-hardening to form a mass with sufficient strength for many medical and dental applications, and (2) when implanted in bone, the material resorbs slowly and is completely replaced by new bone formation with no loss in the volume or integrity of the tissue that receives the implant. See U.S. Pat. Nos. Re. 33,221 and Re. 33,161 to Brown and Chow, which teach preparation of calcium phosphate remineralization compositions and of a finely crystalline, non-ceramic, gradually resorbable hydroxyapatite material based on the same calcium phosphate composition.
A virtually identical calcium phosphate system, which consists of tetracalcium phosphate (TTCP) and monocalcium phosphate (MCP) or its monohydrate form (MCPM) was described by Constantz et al. (U.S. Pat. Nos. 5,053,212 and 5,129,905). This system reportedly involves conversion of the MCP to dicalcium phosphate, which reacts with TTCP and forms hydroxyapatite (HA), the major mineral component of teeth and bone, as the end product.
Another type of calcium phosphate composition comprises an amorphous, apatitic calcium phosphate as a reactant, a promoter, and an aqueous liquid to form a hardening paste. See, e.g., U.S. Pat. Nos. 5,650,176; 5,676,976; 5,683,461; 6,027,742; and 6,117,456 to Lee et al. This system provides a bioactive ceramic material that is biocompatible, bioresorbable and workable for long periods of time at room temperature. The bioactive ceramic material may be formed at low temperatures, is readily formable and/or injectable, and yet can harden to high strength upon further reaction. The bioactive ceramic material contains poorly crystalline apatitic calcium phosphate solids with calcium-to-phosphate (Ca/P) ratios comparable to naturally occurring bone minerals and having stiffness and fracture roughness similar to natural bone. The bioactive ceramic composite material is strongly bioresorbable and its biosorbability and reactivity can be adjusted to meet the demands of the particular therapy and/or implant site. The material may be prepared as bone plates, bone screws and other fixtures and medical devices, including veterinarian applications, which are strongly bioresorbable and/or ossifying.
One of the goals of reconstructive surgery is to be able to replace damaged tissue with new tissue, using either a patient's own cells or growth enhancing proteins. For example, researchers have endeavored to develop cartilage regeneration systems in which isolated chondrocytes are injected into a damaged area in the context of a polymer scaffold (see, e.g., Atala et al., J. Urol. 150:747 (1993); Freed et al., J. Cell. Biochem. 51:257 (1993) and references cited therein). Similar seeded scaffold systems have been studied in the context of bone repair, where osteoblast cells are utilized in conjunction with polymeric or ceramic supports (see, e.g., Elgendy et al., Biomater. 14:263 (1993); Ishaug et al., J. Biomed. Mater. Res. 28:1445 (1994)). Of particular interest are osteoinductive materials such as bone morphogenetic proteins (e.g., recombinant human BMP-2), demineralized bone matrix; transforming growth factors (e.g., TGF-β); and various other organic species known to induce bone formation.
Three general types of calcium phosphate-based scaffold materials have been designed specifically for use with seeded compositions. One type of scaffold material consists of pre-formed calcium phosphate-based granules with the bioactive substance bound on the external surface. In general, large granules (ideally 100-1000 μm) are required to avoid eliciting inflammatory responses. However, such large pre-fabricated granules are not easily injectable through small gauge needles required for percutaneous injection. In addition, factors can only be admixed with preformed granules resulting in surface coating rather than the factor being embedded or dispersed throughout the matrix. Embedding the factor allows for a more controlled release of biomolecules as the matrix is resorbed. Pre-formed granules are typically difficult to handle and apply. Furthermore, most pre-formed hydroxyapatite granules are produced by a sintering process rendering them essentially non-resorbable.
A second type of scaffold material for seeded compositions consists of implantable porous hydroxyapatite or tricalcium phosphate blocks. Implantable porous blocks may be prepared with varying degrees of porosity, typically using a dry mixture of controlled particle size reactants. Other methods of promoting porosity include chemical or physical etching and leaching. Although they generally provide sufficient support, porous blocks have several significant drawbacks. First, like the pre-fabricated granules described above, block scaffolds do not have the osteoinductive substance embedded throughout the volume, and thus prevent controlled release of the active substance. Second, implantable blocks are not injectable, and thus require a more intrusive implantation procedure. Finally, and importantly, monolithic blocks may impede the rate of bone formation for clinical applications where an acceleration of healing is desired over the normal time course of healing. This delay may be due to slow resorption of the solid carrier and subsequent delayed release of the active substance. The presence of the monolithic matrix may also obstruct cell migration and infiltration to the fracture site. Assuming the block matrix contains interconnecting channels between the pores, new bone growth will be dictated by the pores and bounds of the scaffold walls, thus limiting new bone formation.
A third type of scaffold material involves calcium phosphate cements. Unlike the prefabricated granules and monolithic blocks, cements are readily injectable and can have the osteoinductive substance embedded throughout the volume. However, these cements tend to form monolithic aggregates that are inherently microporous. Although macroporous versions using biodegradable pore-formers have been described (see, e.g., PCT publication No. WO 98/16209, which is incorporated herein by reference), these cements form monolithic scaffolds which contain channels rather than microporous granules which, as discussed above, significantly restricts new bone growth.
Accordingly, despite substantial endeavors in this field, there remains a need for a drug delivery vehicle that is biocompatible, readily resorbable, and not detrimental to drug activity. Ideally, the vehicle should be injectable; malleable to enable injection or implantation into various sized fractures and defects; promote homogeneous distribution of bioactive materials throughout the matrix, thus permitting controlled release of the active substance; and, finally, form discrete macrogranules upon administration to the surgical or defective site. Granulation is desirable to facilitate cell migration and infiltration for secretion of extracellular bone matrix, and to provide access for vascularization Granules also provide high surface area for enhanced resorption and release of active substance, as well as increased cell-matrix interaction. The present invention solves these needs, providing materials and compositions useful in drug delivery and in tissue repair.